The present invention relates the novel use of ciclesonide in the treatment of inflammatory bowel diseases and to pharmaceutical compositions containing ciclesonide for the treatment of certain inflammatory bowel diseases.
Inflammatory bowel disease is the term generally applied to two diseases, namely ulcerative colitis and Crohn's disease.
Ulcerative colitis is a chronic inflammatory disease of unknown etiology afflicting only the large bowel and, except when very severe, limited to the bowel mucosa. The course of the disease may be continuous or relapsing, mild or severe. The risk of colon carcinoma has been reported to be elevated after longstanding disease. Ulcerative colitis is curable by total colectomy, which may be needed for acute severe disease or chronic unremitting disease. Most patients with ulcerative colitis are managed medically rather than surgically.
Crohn's disease is also a chronic inflammatory disease of unknown etiology but, unlike ulcerative colitis, it can affect any part of the bowel. Although lesions may start superficially, the inflammatory process extends through the bowel wall to the draining lymph nodes. As with ulcerative colitis, the course of the disease may be continuous or relapsing, mild or severe but, unlike ulcerative colitis it is not curable by resection of the involved segment of bowel. Most patients with Crohn's disease come to surgery at some time, but subsequent relapse is common and continuous medical treatment is usual.
For treatment of acute attacks of ulcerative colitis, glucocorticosteroids such as prednisone or prednisolone acetate are almost invariably used and given parenterally or by mouth for the average acute attack or relapse, or locally, by enema.
Ciclesonide is a novel inhaled corticosteroid for asthma treatment, which is undergoing clinical evaluation. For ciclesonide low systemic side effects have been observed in clinical studies. Ciclesonide has very low affinity for the glucocorticosteroid receptor but is readily converted to the active metabolite desisobutyryl-ciclesonide by esterases in the lung to provide local activity in the target organ. This activation occurs by ester cleavage at the C21 position of ciclesonide. The affinity of desisobutyryl-ciclesonide to the glucocorticosteroid receptor is approximately 100 times higher than that of ciclesonide. Ciclesonide has a low oral bioavailability in the human system, which is below 1%.
Ciclesonide and various other novel glucocorticoids as well as pharmaceutical formulations for ciclesonide are disclosed in
Surprisingly it has been found now that ciclesonide is particularly suitable for the treatment of inflammatory bowel diseases. Unexpectedly with regard to above described properties of ciclesonide it has been found that ciclesonide when administered in particular by the oral route has a great potential benefit in the treatment of inflammatory bowel disease.
Due to its high anti-inflammatory activity and low systemic activity ciclesonide provides a significant benefit and advantage in the treatment of inflammatory bowel disease. In addition, ciclesonide exhibits a high rate of systemic clearance, which prevents it from exerting significant systemic effects. This superior therapeutic ratio compared to other steroids makes ciclesonide particularly suitable for the treatment -in particular for a long term treatment- of inflammatory bowel diseases. In particular due to the low systemic effect ciclesonide may be used in maintenance or long term therapy in the treatment of inflammatory bowel disease providing the benefit of less side effects for the patient in need thereof.
In one aspect the present invention therefore relates to the use of ciclesonide in the manufacturing of a medicament (pharmaceutical composition) for the treatment of inflammatory bowel disease. Ciclesonide is the INN for an active compound having the chemical name [11β,16α-(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna -1,4-diene-3,20-dione. Ciclesonide and its preparation are described in
Inflammatory bowel disease in connection with the invention refers to chronic non-specific inflammatory conditions of the gastrointestinal tract, of which the two major forms are Crohn's disease and ulcerative colitis. Crohn's disease is characterised by thickened areas of the gastrointestinal wall, with inflammation extending through all layers, deep ulceration and fissuring of the mucosa, and the presence of granulomas; affected areas may occur in any part of the gastrointestinal tract, interspersed with areas of relatively normal tissue; the terminal ileum is frequently involved. Symptoms depend on the site of disease but may include abdominal pain, diarrhoea, fever, weight loss, and rectal bleeding. Extra-intestinal manifestations may include joint inflammation, skin lesions, mouth ulcers, and liver disorders. In ulcerative colitis, disease is confined to the colon and rectum, inflammation is superficial but continuous over the affected area, and granulomas are rare. In mild disease, the rectum alone may be affected (proctitis); in severe disease, ulceration is extensive and much of the mucosa may be lost, with an increased risk of toxic dilatation of the colon, a potentially life-threatening complication. Symptoms include diarrhoea and rectal bleeding. The extra-intestinal manifestations are similar to those of Crohn's disease. Patient in connection with the invention preferably refers to a human suffering from an inflammatory bowel disease as defined above.
In another aspect the invention relates to a medicament (herein also referred to as pharmaceutical composition) comprising a therapeutically effective amount of ciclesonide and a pharmaceutically acceptable carrier and/or excipients according to claim 7. The pharmaceutical composition is suitable for oral administration. Pharmaceutical compositions, which may be mentioned are e.g. tablets, coated tablets, capsules, pellets, granulates, emulsions, suspensions or gels.
Excipients suitable for the desired pharmaceutical composition according to the invention are familiar to the person skilled in the art.
In order for the oral composition containing ciclesonide to be applicable for the treatment of the bowel diseases the composition must be adjusted to this particular purpose.
The transit time through the gastro-intestinal canal for different dosage forms are rather well known. When the dosage form has been emptied from the stomach the transit through the small intestine takes 3 to 5 hours. The residence time in the large intestine is considerably longer, 25 to 50 hours. Ideally, as long as the dosage form remains in the stomach no release should occur. If Crohn's disease in small intestine is going to be treated the release should start after the dosage form has left the stomach and if necessary, should continue during about 3 to 5 hours after the dosage form has left the stomach. If the large intestine is going to be treated the release should ideally start at the distal small intestine oar at caecum, if necessary, followed by slow release of ciclesonide. Ciclesonide must have a chance to reach the inflamed part of the bowel in sufficient concentration and for a sufficient long time to exert it's local action, in the case of Crohn's disease the whole bowel or only the small intestine and in the case of ulcerative colitis the caecum (cecum), colon and the rectum.
In ulcerative colitis, the composition should be formulated so that ciclesonide is released preferentially during the passage of the colon. In Crohn's disease in the ileum the composition should be formulated so that the ciclesonide is released preferentially during the passage of the small intestine.
Such formulations designed for the treatment of inflammatory diseases allowing for targeted release in the small intestine and colon can be prepared by enteric and slow release coating of the units containing ciclesonide. Preferably ciclesonide is contained in a core formulation releasing the drug substance immediately. Such core formulations can be granulates, pellets or tablets. By coating these core formulations with at least one enteric and at least one slow release coating the desired release profile can be obtained. Pharmaceutically acceptable excipients for enteric coating being insoluble at gastric pH but soluble at intestinal pH include cellulose acetate phthalate, hydroxpropylmethyl-cellulose phthalate, polyvinylacetate phthalate and acrylic acid polymers e.g. partly esterified methacrylic acid polymers such as Eudragit L, Eudragit L1 00-55 and Eudragit S. The acrylic polymers can also be used as commercially available aqueous dispersions, e.g. Eudragit FS30D Eudragit L30 D55. These polymers may be used alone or in combination with each other. In order to obtain an acceptable film coat other excipients such as plasticizers, anti-adhesives and antifoaming agents can be added.
The release profile of the coated formulation can be altered by varying the coating thickness as well as the composition of the coating. If slow release of ciclesonide is desired in the targeted regions of the GI tract, mixtures of enteric coatings with slow release coatings can be applied. This can be done by only one single coating layer or in two or more separate layers. The polymers of this coating can be selected from cellulose derivatives and copolymers of methacrylic acid esters such as ethylcellulose and Eudragit NE, Eudragit RL and Eudragit RS. These polymers are also commercially available in form of aqueous dispersions. In order to obtain an acceptable film coat other excipients such as plasticizers, anti-adhesives and antifoaming agents can be added. The release profile of the coated formulation can the altered by varying the coating thickness as well as the composition of the coating.
The core formulation can be prepared employing excipients known for those being skilled in the art: Fillers such as lactose, mannitol, calcium phosphate, microcrystalline cellulose, sucrose, starch, waxes and lipids. Binders such as hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, starch and its derivatives as well as wetting agents, surfactants and disintegrants. In case of pellets sugar spheres can be used as seed material.
The manufacturing of these formulations is done by processes usually employed for manufacturing of solid oral dosage forms such as granulation by high shear mixing, roller compaction for fluidized bed, preparation of pellets by extrusion spheronisation or layering on seed pellets and compression of powders to tablets. The coating can be done in a fluidized bed process or in a conventional pan or drum coating process by spraying an aqueous or organic fluid.
Suitable dosage forms for targeted release are for example described in
The dosage range for treatment of the bowel diseases as hereinbefore defined is suitably within the general dosage range and regimen for glucocorticosteroids in the treatment of bowel disease. Suitable dosage ranges for budesonide are e.g. disclosed in
The production of oral administration forms of ciclesonide for targeted release in the treatment of inflammatory bowel disease is described by way of example below. The following examples illustrate the invention in greater detail, without restricting it.
Performed as described in example 1, step 1.
Performed as described in example 1, step 1.
Tablet and liquid for the preparation of a suspension for rectal application
As an animal model of Inflammatory Bowel Disease, the TNBS-induced Colitis in the rat had been used.
48 h fasted rats (220-250g b.w.) received rectally 0,9 ml of a solution consisting of 30% ethanol, 30 mg/kg TNBS (Trinitrobenzoesulfonic acid) in an oral distance of 8-9 cm from the anus. Compound administration days -1 to +2. Animals were sacrified on day 2.
For intrarectal administration the compounds were solved in 1% ethanol, 10% Propyleneglycol and 20% Cyclodextrin. The used range of concentrations was identical for all compounds. Intrarectal administration schedule: twice daily. Compounds used: Ciclesonide and for comparison, Budesonide and Dexamethasone.
As parameters for the estimation of the pharmacological effects of the compounds, max. colon width had been used. As for the estimation of potential side effects, the weights of thymus and adrenal glands have been registrated.
The efficacy of a treatment was calculated on the reference of controls that received either no TNBS or TNBS rectally, establishing the range of 100 to 0% inhibition, respectively, in the drug screening.
The results indicate the lowest doses of compounds that impact the indicated parameters to a relevant extent:
None of the doses of any of the three compounds tested yielded 100% efficacy in this model. Maximally observed effects on the colon width are between 30 and 60%.
The results demonstrate the efficacy of ciclesonide, attenuating the TNBS-increased colon width starting with 2,3 µmol/animal. At the highest assessed dose of 6,9 µmol/animal, no additional decrease of the TNBS-reduced thymus weight could be detected. Instead, the TNBS-increased adrenal glands weight was attenuated starting with 2,3 µmol/animal ciclesonide.
By contrast, budenoside seems to additionally reduce the thymus weight starting with 2,3 µmol/animal and does not reverse the inhibitory effect of TNBS-treatment on the adrenal glands weight in the assessed pharmacodynamic dose range.
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.